CETP and SGLT2 inhibitor combination therapy improves glycemic control

Area of Science:

• Metabolic disease research
• Pharmacological interventions
• Genetic epidemiology

Background:

• Cholesteryl ester transfer protein (CETP) inhibition shows potential for repurposing in metabolic diseases, possibly as an oral add-on therapy.
• Existing cardiovascular trials noted decreased new-onset diabetes risk with CETP inhibitors.
• Oral CETP inhibitors could supplement sodium-glucose cotransporter 2 (SGLT2) inhibitors, potentially delaying the need for injectable medications like insulin.

Approach:

• A 2x2 factorial Mendelian Randomization (MR) study was conducted using UK Biobank data from 233,765 European ancestry participants.
• Genetic scores for CETP and SGLT2 function were combined to analyze the effects of joint inhibition versus individual inhibition.
• The study assessed associations with glycated hemoglobin levels and type-2 diabetes incidence.

Key Points:

• Joint genetic inhibition of CETP and SGLT2 was associated with significantly lower glycated hemoglobin levels compared to control, SGLT2 inhibition alone, and CETP inhibition alone.
• Combined CETP and SGLT2 inhibition showed a reduced incidence of type-2 diabetes compared to control and SGLT2 inhibition alone.
• The observed effects were statistically significant, with clear effect sizes and confidence intervals reported for both outcomes.

Conclusions:

• CETP and SGLT2 inhibitor therapy may offer superior glycemic control compared to SGLT2 inhibitors alone.
• Further clinical trials are warranted to explore the repurposing of CETP inhibitors for metabolic diseases.
• This combination therapy presents a potential oral treatment option, possibly delaying the need for injectable therapies in high-risk patients.